Project Summary/Abstract Defining brain circuits and neuromodulators that control internal states of motivation, arousal and reward is an important problem in neuroscience with high relevance to human health, including drug abuse and addiction. It is likely that these disorders involve maladaptive changes in natural reward systems. Studies of reward in mammalian systems have focused on the mesolimbic dopamine system. However it is becoming clear that reward involves more than dopamine, and that reward systems are multi-faceted and diverse. The complexity and size of the mammalian central nervous system presents a challenge to systematic identification of novel circuits and neuromodulators mediating arousal, motivation or reward-related states. Invertebrate model organisms such as Drosophila, because of their simpler nervous systems and powerful genetics, allow a function-driven, unbiased approach to this problem. Because reward systems are evolutionarily ancient, such studies may uncover fundamental and general principles that apply to vertebrates as well. However studies of reward in Drosophila have been limited to feeding, which is a homeostatic process, and drugs of abuse, which are not natural rewards. There is, therefore, a need for alternative, non-homeostatic models for natural reward- related states. To fill this gap, we are studying brain mechanisms underlying natural reward states associated with social behaviors. Our broad, long-term objective is to understand how these persistent internal states emerge from interactions between neuromodulators and neural circuits, and whether different reward states utilize distinct or common mechanisms. The central objective of this proposal is to determine how neuromodulators and P1 interneurons, a central hub in a social behavior network, interact to control a persistent internal state that facilitates such behaviors. The rationale for this research is that the study of brain mechanisms controlling this internal state is likely to yield general principles of reward-related neural circuit function. To achieve our objective, we will identify neurons that are a functional target of neuromodulation by octopamine in social arousal (Aim 1); establish the functional relationship between these neurons and P1 interneurons in social behavior (Aim 2); test the hypothesis that P1 neuron activation is positively valenced and rewarding (Aim 3); investigate neuromodulatory mechanisms involved in a novel reward learning paradigm involving P1 neurons (Aim 4). The contribution will be to apply state-of-the-art genetically based tools to dissect the mechanisms that control a novel, natural reward-related internal state. This contribution is significant because it will open up a new system for the study of reward mechanisms in a powerful genetic model organism. The contribution is innovative, because it applies novel methods for imaging and manipulating neural circuit function to dissect a natural reward state that has not been extensively studied. The work proposed in this application will therefore both advance our understanding of fundamental brain mechanisms of motivation, arousal and reward states, and may provide new insights relevant to drug abuse and addiction.